Exploration of novel non-purine xanthine oxidase inhibitors based on oxadiazolones by an integrated simulation study

Abstract

Xanthine oxidase (XO) is a significant target for developing novel drugs to treat hyperuricemia and/or gout. Recently, a series of novel non-purine XO inhibitors (XOIs), 3-[4-alkoxy-3-H/(1-H-tetrazol-1-yl) phenyl]-1,2,4-oxadiazol-5(4H)-ones and 3-(1-alkyl-3-cyano-indole-5-yl)-1,2,4-oxadiazol-5(4H)-ones, have been reported based on bioisosterism and hybridization strategies. In the present study, a systematic computational study was conducted to investigate the structure–activity relationships (SARs) and action mechanisms of these novel XOIs, including three-dimensional quantitative SAR (3D-QSAR) modeling, pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulations. The constructed 3D-QSAR models exhibited excellent predictive ability, with reasonable parameters for comparative molecular field analysis (q² = 0.931, r² = 0.997, and r_pre² = 0.860) and comparative molecular similarity index analysis (q² = 0.930, r² = 0.993, and r_pre² = 0.827). The docking results indicated that amino acid residues Asn768, Arg880, and Thr1010 in the binding site of XO were essential for the affinities of these XOIs. Five potential XOI hits were subsequently identified through combined virtual screening using molecular docking, the optimal pharmacophore model, and ADMET prediction. Furthermore, their binding stabilities in the active cavity were confirmed using MD simulations. This study employed SAR analysis and multiple virtual screenings to identify several promising XOI hits, providing valuable theoretical insights for the design and development of novel XOIs.